Objective： Axenfeld-Rieger syndrome （ARS） is phenotypically and genetically heterogeneous. In this study we identified the underlying genetic defect in a Chinese family with ARS. Methods： A detailed family history...Objective： Axenfeld-Rieger syndrome （ARS） is phenotypically and genetically heterogeneous. In this study we identified the underlying genetic defect in a Chinese family with ARS. Methods： A detailed family history and clinical data were recorded. The ocular phenotype was documented using slit-lamp photography and systemic anomalies were also documented where available. The genomic DNA was extracted from peripheral blood leukocytes. All coding exons and intron-exon junctions of paired-like homeodomain transcription factor 2 （PITX2） gene and the forkhead box C1 （FOXC1） gene were amplified by polymerase chain reaction （PCR） and screened for mutation by direct DNA sequencing. Variations detected in exon 5 of PITX2 were further evaluated with cloning sequencing. The exon 5 of PITX2 was also sequenced in 100 healthy controls, unrelated to the family, for comparison. Structural models of the wild type and mutant homeodomain of PITX2 were investigated by SWISS-MODEL. Results： Affected individuals exhibited variable ocular phenotypes, whereas the systemic anomalies were similar. After direct sequencing and cloning sequencing, a heterozygous deletion/insertion mutation c. 198_201delinsTTTCT （p.M661fs＊133） was revealed in exon 5 of PITX2. This mutation co-segregated with all affected individuals in the family and was not found either in unaffected family members or in 100 unrelated controls. Conclusions： We detected a novel frameshift mutation p.M661fs＊133 in PITX2 in a Chinese family with ARS. Although PITX2 mutations and polymorphisms have been re- ported from various ethnic groups, we report for the first time the identification of a novel deletion/insertion mutation that causes frameshift mutation in the homeodomain of PITX2 protein.展开更多
Ischemic stroke is the second leading cause of death worldwide with limited medications and neuroinflammation was recognized as a critical player in the progression of stroke,but how to control the overactive neuroinf...Ischemic stroke is the second leading cause of death worldwide with limited medications and neuroinflammation was recognized as a critical player in the progression of stroke,but how to control the overactive neuroinflammation is still a long-standing challenge.Here,we designed a novel SIRT6 activator MDL-811 which remarkably inhibited inflammatory response in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages and primary mouse microglia,which were abolished by silencing SIRT6.RNA-seq screening identified the forkhead box C1 (Foxc1) is a key gene evoked by MDL-811stimulation and is required for the anti-inflammatory effects of MDL-811.We found MDL-811-activated SIRT6 directly interacted with enhancer of zeste homolog 2 (EZH2) and promoted deacetylation of EZH2 which could bind to the promoter of Foxc1 and upregulate its expression to modulate inflammation.Moreover,our data demonstrated that MDL-811 not only ameliorated sickness behaviors in neuroinflammatory mice induced by LPS,but also markedly reduced the brain injury in ischemic stroke mice in addition to promoting long-term functional recovery.Importantly,MDL-811 also exhibited strong anti-inflammatory effects in human monocytes isolated from ischemic stroke patients,underlying an interesting translational perspective.Taken together,MDL-811 could be an alternative therapeutic candidate for ischemic stroke and other brain disorders associated with neuroinflammation.展开更多
基金Project supported by the Qianjiang Talents Project of Zhejiang Province(No.2010R10067)the Zhejiang Key Innovation Team Project of China(No.2009R50039)the Zhejiang Key Laboratory Foundation of China(No.2011E10006)
文摘Objective： Axenfeld-Rieger syndrome （ARS） is phenotypically and genetically heterogeneous. In this study we identified the underlying genetic defect in a Chinese family with ARS. Methods： A detailed family history and clinical data were recorded. The ocular phenotype was documented using slit-lamp photography and systemic anomalies were also documented where available. The genomic DNA was extracted from peripheral blood leukocytes. All coding exons and intron-exon junctions of paired-like homeodomain transcription factor 2 （PITX2） gene and the forkhead box C1 （FOXC1） gene were amplified by polymerase chain reaction （PCR） and screened for mutation by direct DNA sequencing. Variations detected in exon 5 of PITX2 were further evaluated with cloning sequencing. The exon 5 of PITX2 was also sequenced in 100 healthy controls, unrelated to the family, for comparison. Structural models of the wild type and mutant homeodomain of PITX2 were investigated by SWISS-MODEL. Results： Affected individuals exhibited variable ocular phenotypes, whereas the systemic anomalies were similar. After direct sequencing and cloning sequencing, a heterozygous deletion/insertion mutation c. 198_201delinsTTTCT （p.M661fs＊133） was revealed in exon 5 of PITX2. This mutation co-segregated with all affected individuals in the family and was not found either in unaffected family members or in 100 unrelated controls. Conclusions： We detected a novel frameshift mutation p.M661fs＊133 in PITX2 in a Chinese family with ARS. Although PITX2 mutations and polymorphisms have been re- ported from various ethnic groups, we report for the first time the identification of a novel deletion/insertion mutation that causes frameshift mutation in the homeodomain of PITX2 protein.
基金supported by the National Natural Science Foundation of China (81973512, 81925034, 81701235, and 81991514)Double First-Class Project of China Pharmaceutical University(CPU2018GY06 and CPU2018GY20, China)+1 种基金the Fundamental Research Funds for the Central Universities(021414380446, China)supported by the Six Talent Peaks Project of Jiangsu Province (China) to Tao Pang。
文摘Ischemic stroke is the second leading cause of death worldwide with limited medications and neuroinflammation was recognized as a critical player in the progression of stroke,but how to control the overactive neuroinflammation is still a long-standing challenge.Here,we designed a novel SIRT6 activator MDL-811 which remarkably inhibited inflammatory response in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages and primary mouse microglia,which were abolished by silencing SIRT6.RNA-seq screening identified the forkhead box C1 (Foxc1) is a key gene evoked by MDL-811stimulation and is required for the anti-inflammatory effects of MDL-811.We found MDL-811-activated SIRT6 directly interacted with enhancer of zeste homolog 2 (EZH2) and promoted deacetylation of EZH2 which could bind to the promoter of Foxc1 and upregulate its expression to modulate inflammation.Moreover,our data demonstrated that MDL-811 not only ameliorated sickness behaviors in neuroinflammatory mice induced by LPS,but also markedly reduced the brain injury in ischemic stroke mice in addition to promoting long-term functional recovery.Importantly,MDL-811 also exhibited strong anti-inflammatory effects in human monocytes isolated from ischemic stroke patients,underlying an interesting translational perspective.Taken together,MDL-811 could be an alternative therapeutic candidate for ischemic stroke and other brain disorders associated with neuroinflammation.
